Ultra Long Protokol

Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogs. Annu Rev Med. 1994; 45:391-405.

Mendoza-Valdés A. Introduction of Dr. Andrew V Schally. Asian J Androl. 2015 Nov–Dec;17(6):923–4. doi:10.4103/1008-682X.156852.

Flanagan CA, Manilall A. Gonadotropin-releasing hormone (GnRH) receptor structure and GnRH binding. Front Endocrinol. 2017;1–14. doi.org/10.3389/fendo.2017.00274

Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev.2004; 25:235-275. doi.org/10.1210/er.2003-0002

Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II and their receptors in humans. Endocr Rev. 2005 Apr;26(2):283–306. doi.org/10.1210/er.2003-0039

Desaulniers AT, White BR. Role of gonadotropin-releasing hormone 2 and its receptor in human reproductive cancers. Front Endocrinol. 2024; 14:1-10. doi.org/10.3389/fendo.2023.1341162

Furman B. Gonadotropin Releasing Hormone Agonists, Comprehensive Medicinal Chemistry, Elsevier, 2007.

Speroff L. Clinical Gynecologic Endocrinology an Infertility, In Vitro Fertilization and Embryo transfer. Lippincott Williams&Wilkins, Chapter 97 sf:3-4, 2025

Saleh FL, Taylor HS. Clinical applications of gonadotropin-releasing hormone analogues: a broad impact on reproductive medicine. Fertil Steril Rep. 2023;4(2):83–87. doi.org/10.1016/j.xfre.2023.01.008

Meresman GF, Bilotas MA, Lombardi E, Tesone M, Sueldo C, Barañao RI. Effect of GnRH analogues on apoptosis and release of interleukin-1β and vascular endothelial growth factor in endometrial cell cultures from patients with endometriosis. Hum Reprod. 2003 Sep;18(9):1767–1771. doi.org/10.1093/humrep/deg356

Donnez J, Smoes P, Gillerot S, et al. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998; 13:1686–1690. doi.org/10.1093/humrep/13.6.1686

Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25(3):642–653. doi.org/10.1093/humrep/dep437

Tamura, Hiroshi, et al. "A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis." Journal of ovarian research 7 (2014): 1-6.

Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Fertil Steril. 1990; 54:419–427. doi.org/10.1016/S0015-0282(16)53755-8

Batzer FR. GnRH analogs: Options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006;13(6):539–545. doi.org/10.1016/j.jmig.2006.07.007

Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000; 74:534–539. doi.org/10.1016/S0015-0282(00)00690-7

Kumar P, Sharma A. Gonadotropin-releasing hormone analogs: Understanding advantages and limitations. J Hum Reprod Sci. 2014 Jul–Sep;7(3):170–174. doi:10.4103/0974-1208.142476.

Creus M, Ordi J, Fabregues F, Casairijana R, Carmona F, Cardesa A, et al. The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study. Hum Reprod. 2003; 18:683–693. doi.org/10.1093/humrep/deg177

Lindhard A, Beutin-Ley U, Raun V, Islin H, Hoiid T, Rex S, et al. Biochemical evaluation of endometrial function at the time of implantation. Fertil Steril. 2002; 78:221–233. doi.org/10.1016/S0015-0282(02)03240-5

Lessey B. Medical management of endometriosis and infertility. Fertil Steril. 2000; 73:1089–1096. doi.org/10.1016/S0015-0282(00)00519-7

Li L, Chen X, Zhao L, et al. GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regimen in frozen embryo transfer cycles. Reprod Biol. 2022;22(2):100608. doi.org/10.1016/j.repbio.2022.100608

Gong F, Xia E, Zhang S, et al. A modified ultra-long pituitary downregulation protocol improved endometrial receptivity and clinical outcome for infertile patients with polycystic ovarian syndrome. Exp Ther Med. 2015;10(5):1865–1870. doi.org/10.3892/etm.2015.2769

Cao X, Chang H, Xu J, et al. The effectiveness of different down-regulating protocols on in vitro fertilization–embryo transfer in endometriosis: a meta-analysis. Reprod Biol Endocrinol. 2020; 18:16. doi.org/10.1186/s12958-020-00571-6

Tomassetti C, Beukeleirs T, Conforti A, et al. The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis. Hum Reprod. 2021 Oct;36(10):2676–2686. doi.org/10.1093/humrep/deab163

Kuan KKW, Omoseni S, Tello JA. Comparing ART outcomes in women with endometriosis after GnRH agonist versus GnRH antagonist ovarian stimulation: a systematic review. Ther Adv Endocrinol Metab. 2023;14. doi:10.1177/20420188231173325

Ge L, Li Y, Zhou J, et al. Effect of different treatment protocols on in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes in adenomyosis women:a systematic review and meta-analysis. BMJ Open. 2024;14: e077025.doi:10.1136/bmjopen-2023-077025

Sallam HN, Garcia-Velasco JA, Dias S, et al. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006;(1):CD004635. doi: 10.1002/14651858.CD004635.pub2

Rodríguez-Tárrega E, Monzo AM, Quiroga R, et al. Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial. Reprod Biomed Online. 2020;41(4):653–662. doi.org/10.1016/j.rbmo.2020.06.020

Kaponis A, Chatzopoulos G, Paschopoulos M, et al. Ultralong administration of gonadotropin-releasing hormone agonists before in vitro fertilization improves fertilization rate but not clinical pregnancy rate in women with mild endometriosis: a prospective, randomized, controlled trial. Fertil Steril. 2020;113(4):828–835. doi.org/10.1016/j.fertnstert.2019.12.018

Georgiou EX, Melo P, Baker PE, et al. Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis. Cochrane Database Syst Rev. 2019. doi: 10.1002/14651858.CD013240.pub2

Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. Hum Reprod Open. 2022;2022(2):hoac 009. doi.org/10.1093/hropen/hoac009

Vercellini P, Viganò P, Bandini V, Buggio L, Berlanda N, Somigliana E. Association of endometriosis and adenomyosis with pregnancy and infertility. Fertil Steril. 2023;119(5):727–740. doi.org/10.1016/j.fertnstert.2023.03.018

Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014; 29:964–977. doi.org/10.1093/humrep/deu041

Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Ishimaru T, et al. Cell proliferation effect of GnRH agonist on pathological lesions of women with endometriosis, adenomyosis and uterine myoma. Hum Reprod. 2010; 25:2878–2890. doi.org/10.1093/humrep/deq240

Hou X, Xing J, Shan H, Mei J, Sun Y, Yan G, et al. The effect of adenomyosis on IVF after long or ultra-long GnRH agonist treatment. Reprod Biomed Online. 2020;41(5):845–853. doi.org/10.1016/j.rbmo.2020.07.027

Wang Y, Yi YC, Guu HF, Chen YF, Kung HF, Chang JC, et al. Impact of adenomyosis and endometriosis on IVF/ICSI pregnancy outcome in patients undergoing gonadotropin-releasing hormone agonist treatment and frozen embryo transfer. Sci Rep. 2023;13(1):6741. doi.org/10.1038/s41598-023-34045-7

Ansaripour S, Yazdchi K, Sadeghi MR, Nasseri N, Karimi A, Ataei M, et al. Comparison of ultra-long gonadotropin releasing hormone agonist versus standard downregulation in women with adenomyosis undergoing frozen-thawed embryo transfer: a randomized clinical trial. Contracept Reprod Med. 2024;9(1):44. doi.org/10.1186/s40834-024-00304-9

Latif S, Kastora S, Al Wattar BH, Yasmin E, Saridogan E, Mavrelos D. The effectiveness of prolonged downregulation with gonadotrophin-releasing hormone analogue (GnRHa) treatment in women with adenomyosis undergoing IVF/ICSI: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2024. doi.org/10.1016/j.ejogrb.2024.07.063

Cozzolino M, Pellicer N, Galliano D, Pellicer A. Pituitary suppression with GnRH agonists before ART may be insufficient to treat women with severe adenomyosis. Reprod Biomed Online. 2023;46(1):150–155. doi.org/10.1016/j.rbmo.2022.09.023

Tu J, Lin G, Lu C, Gong F. A novel modified ultra-long agonist protocol improves the outcome of high body mass index women with polycystic ovary syndrome undergoing IVF/ICSI. Gynecol Endocrinol. 2014 Mar;30(3):209–212. doi.org/10.3109/09513590.2013.860121

Gong F, Li X, Zhang S, Ma H, Cai S, Li J, Lin G. A modified ultra-long pituitary downregulation protocol improved endometrial receptivity and clinical outcome in infertile patients with polycystic ovarian syndrome. Exp Ther Med. 2015; 10:1865–1870. doi.org/10.3892/etm.2015.2769

Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogs. Annu Rev Med. 1994; 45:391-405.

Mendoza-Valdés A. Introduction of Dr. Andrew V Schally. Asian J Androl. 2015 Nov–Dec;17(6):923–4. doi:10.4103/1008-682X.156852.

Flanagan CA, Manilall A. Gonadotropin-releasing hormone (GnRH) receptor structure and GnRH binding. Front Endocrinol. 2017;1–14. doi.org/10.3389/fendo.2017.00274

Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev.2004; 25:235-275. doi.org/10.1210/er.2003-0002

Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II and their receptors in humans. Endocr Rev. 2005 Apr;26(2):283–306. doi.org/10.1210/er.2003-0039

Desaulniers AT, White BR. Role of gonadotropin-releasing hormone 2 and its receptor in human reproductive cancers. Front Endocrinol. 2024; 14:1-10. doi.org/10.3389/fendo.2023.1341162

Furman B. Gonadotropin Releasing Hormone Agonists, Comprehensive Medicinal Chemistry, Elsevier, 2007.

Speroff L. Clinical Gynecologic Endocrinology an Infertility, In Vitro Fertilization and Embryo transfer. Lippincott Williams&Wilkins, Chapter 97 sf:3-4, 2025

Saleh FL, Taylor HS. Clinical applications of gonadotropin-releasing hormone analogues: a broad impact on reproductive medicine. Fertil Steril Rep. 2023;4(2):83–87. doi.org/10.1016/j.xfre.2023.01.008

Meresman GF, Bilotas MA, Lombardi E, Tesone M, Sueldo C, Barañao RI. Effect of GnRH analogues on apoptosis and release of interleukin-1β and vascular endothelial growth factor in endometrial cell cultures from patients with endometriosis. Hum Reprod. 2003 Sep;18(9):1767–1771. doi.org/10.1093/humrep/deg356

Donnez J, Smoes P, Gillerot S, et al. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998; 13:1686–1690. doi.org/10.1093/humrep/13.6.1686

Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25(3):642–653. doi.org/10.1093/humrep/dep437

Tamura, Hiroshi, et al. "A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis." Journal of ovarian research 7 (2014): 1-6.

Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Fertil Steril. 1990; 54:419–427. doi.org/10.1016/S0015-0282(16)53755-8

Batzer FR. GnRH analogs: Options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006;13(6):539–545. doi.org/10.1016/j.jmig.2006.07.007

Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000; 74:534–539. doi.org/10.1016/S0015-0282(00)00690-7

Kumar P, Sharma A. Gonadotropin-releasing hormone analogs: Understanding advantages and limitations. J Hum Reprod Sci. 2014 Jul–Sep;7(3):170–174. doi:10.4103/0974-1208.142476.

Creus M, Ordi J, Fabregues F, Casairijana R, Carmona F, Cardesa A, et al. The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study. Hum Reprod. 2003; 18:683–693. doi.org/10.1093/humrep/deg177

Lindhard A, Beutin-Ley U, Raun V, Islin H, Hoiid T, Rex S, et al. Biochemical evaluation of endometrial function at the time of implantation. Fertil Steril. 2002; 78:221–233. doi.org/10.1016/S0015-0282(02)03240-5

Lessey B. Medical management of endometriosis and infertility. Fertil Steril. 2000; 73:1089–1096. doi.org/10.1016/S0015-0282(00)00519-7

Li L, Chen X, Zhao L, et al. GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regimen in frozen embryo transfer cycles. Reprod Biol. 2022;22(2):100608. doi.org/10.1016/j.repbio.2022.100608

Gong F, Xia E, Zhang S, et al. A modified ultra-long pituitary downregulation protocol improved endometrial receptivity and clinical outcome for infertile patients with polycystic ovarian syndrome. Exp Ther Med. 2015;10(5):1865–1870. doi.org/10.3892/etm.2015.2769

Cao X, Chang H, Xu J, et al. The effectiveness of different down-regulating protocols on in vitro fertilization–embryo transfer in endometriosis: a meta-analysis. Reprod Biol Endocrinol. 2020; 18:16. doi.org/10.1186/s12958-020-00571-6

Tomassetti C, Beukeleirs T, Conforti A, et al. The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis. Hum Reprod. 2021 Oct;36(10):2676–2686. doi.org/10.1093/humrep/deab163

Kuan KKW, Omoseni S, Tello JA. Comparing ART outcomes in women with endometriosis after GnRH agonist versus GnRH antagonist ovarian stimulation: a systematic review. Ther Adv Endocrinol Metab. 2023;14. doi:10.1177/20420188231173325

Ge L, Li Y, Zhou J, et al. Effect of different treatment protocols on in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes in adenomyosis women:a systematic review and meta-analysis. BMJ Open. 2024;14: e077025.doi:10.1136/bmjopen-2023-077025

Sallam HN, Garcia-Velasco JA, Dias S, et al. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006;(1):CD004635. doi: 10.1002/14651858.CD004635.pub2

Rodríguez-Tárrega E, Monzo AM, Quiroga R, et al. Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial. Reprod Biomed Online. 2020;41(4):653–662. doi.org/10.1016/j.rbmo.2020.06.020

Kaponis A, Chatzopoulos G, Paschopoulos M, et al. Ultralong administration of gonadotropin-releasing hormone agonists before in vitro fertilization improves fertilization rate but not clinical pregnancy rate in women with mild endometriosis: a prospective, randomized, controlled trial. Fertil Steril. 2020;113(4):828–835. doi.org/10.1016/j.fertnstert.2019.12.018

Georgiou EX, Melo P, Baker PE, et al. Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis. Cochrane Database Syst Rev. 2019. doi: 10.1002/14651858.CD013240.pub2

Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. Hum Reprod Open. 2022;2022(2):hoac 009. doi.org/10.1093/hropen/hoac009

Vercellini P, Viganò P, Bandini V, Buggio L, Berlanda N, Somigliana E. Association of endometriosis and adenomyosis with pregnancy and infertility. Fertil Steril. 2023;119(5):727–740. doi.org/10.1016/j.fertnstert.2023.03.018

Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014; 29:964–977. doi.org/10.1093/humrep/deu041

Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Ishimaru T, et al. Cell proliferation effect of GnRH agonist on pathological lesions of women with endometriosis, adenomyosis and uterine myoma. Hum Reprod. 2010; 25:2878–2890. doi.org/10.1093/humrep/deq240

Hou X, Xing J, Shan H, Mei J, Sun Y, Yan G, et al. The effect of adenomyosis on IVF after long or ultra-long GnRH agonist treatment. Reprod Biomed Online. 2020;41(5):845–853. doi.org/10.1016/j.rbmo.2020.07.027

Wang Y, Yi YC, Guu HF, Chen YF, Kung HF, Chang JC, et al. Impact of adenomyosis and endometriosis on IVF/ICSI pregnancy outcome in patients undergoing gonadotropin-releasing hormone agonist treatment and frozen embryo transfer. Sci Rep. 2023;13(1):6741. doi.org/10.1038/s41598-023-34045-7

Ansaripour S, Yazdchi K, Sadeghi MR, Nasseri N, Karimi A, Ataei M, et al. Comparison of ultra-long gonadotropin releasing hormone agonist versus standard downregulation in women with adenomyosis undergoing frozen-thawed embryo transfer: a randomized clinical trial. Contracept Reprod Med. 2024;9(1):44. doi.org/10.1186/s40834-024-00304-9

Latif S, Kastora S, Al Wattar BH, Yasmin E, Saridogan E, Mavrelos D. The effectiveness of prolonged downregulation with gonadotrophin-releasing hormone analogue (GnRHa) treatment in women with adenomyosis undergoing IVF/ICSI: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2024. doi.org/10.1016/j.ejogrb.2024.07.063

Cozzolino M, Pellicer N, Galliano D, Pellicer A. Pituitary suppression with GnRH agonists before ART may be insufficient to treat women with severe adenomyosis. Reprod Biomed Online. 2023;46(1):150–155. doi.org/10.1016/j.rbmo.2022.09.023

Tu J, Lin G, Lu C, Gong F. A novel modified ultra-long agonist protocol improves the outcome of high body mass index women with polycystic ovary syndrome undergoing IVF/ICSI. Gynecol Endocrinol. 2014 Mar;30(3):209–212. doi.org/10.3109/09513590.2013.860121

Gong F, Li X, Zhang S, Ma H, Cai S, Li J, Lin G. A modified ultra-long pituitary downregulation protocol improved endometrial receptivity and clinical outcome in infertile patients with polycystic ovarian syndrome. Exp Ther Med. 2015; 10:1865–1870. doi.org/10.3892/etm.2015.2769